Preproinsulin is synthesized in the rough endoplasmic reticulum from insulin mRNA and delivered to the Golgi apparatus. There, a series of proteolytic cleavage steps generate mature insulin and a cleavage peptide, C-peptide. Both insulin and C-peptide are then stored in secretory granules and secreted in equimolar quantities after physiologic stimulation

What is the change in C-peptide in DM1 and 2?

decreases/increases

What is the most important regulator of insulin?

Glucose

How does glucose regulate insulin secretion?

A rise in blood glucose levels results in glucose uptake into pancreatic β cells, facilitated by an insulin- independent glucose-transporter, GLUT-2. β cells express an ATP-sensitive K+ channel on the membrane, which comprises two subunits: an inward rectifying K+ channel (Kir6.2) and the sulfonylurea receptor (SUR1). Metabolism of glucose by glycolysis generates ATP, resulting in an increase in β-cell cytoplasmic ATP/ADP ratios. This inhibits the activity of the ATP-sensitive K+ channel, leading to membrane depolarization and the influx of extracellular Ca[2]+ through voltage-dependent Ca[2]+ channels. The resultant increase in intracellular Ca[2]+ stimulates secretion of insulin, presumably from stored hormone within the β-cell granules. This is the phase ofimmediate release of insulin. If the secretory stimulus persists, a delayed and protracted response follows that involves active synthesis of insulin.

Factors other than glucose that stimulate insulin do this by primarily increasing insulin.........

Release (not synthesis)

What is the major metabolic function of insulin?

To increase the rate of glucose transport into certain cells in the body, thus providing an increased source of energy

4. Mitogenic (initiation of DNA synthesis in certain cells and stimulation of their growth and differentiation)

What is the mechanism of action of insulin receptor?

The insulin receptor is a tetrameric protein composed of two α- and two βsubunits. The β-subunit cytosolic domain possesses tyrosine kinase activity. Insulin binding to the α-subunit extracellular domain activates the β-subunit tyrosine kinase, resulting in autophosphorylation of the receptor and the phosphorylation (activation) of several intracellular substrate proteins, such as the family of insulin receptor substrate (IRS) proteins, which includes IRS1–IRS4 and GAB1. The substrate proteins, in turn, activate multiple downstream signaling cascades, including the PI-3K and the MAP kinase pathways, which mediate the metabolic and mitogenic activities of insulin on the cell. Insulin signaling facilitates the trafficking and docking of vesicles containing the glucose transporter protein GLUT-4 to the plasma membrane, which promotes glucose uptake. This process is mediated by AKT, the principal effector of the PI-3K pathway, but also independently by the cytoplasmic protein CBL, which is a direct phosphorylation target of the insulin receptor.

Polymorphisms in CTLA4 and PTPN22 (also in autoimmune thyroiditis). Both CTLA-4 and PTPN-22 are thought to inhibit T-cell responses--> decreased activation

Polymorphism is in CD25 (α chain of the IL-2 receptor)--> decreased activation

What are the possible explanations of viral involvement in DM1?

1. The first is “bystander” damage, wherein viral infections induce islet injury and inflammation, leading to the release of sequestered β-cell antigens and the activation of autoreactive T cells.

2. The second possibility is that the viruses produce proteins that mimic β-cell antigens, and the immune response to the viral protein cross-reacts with the self-tissue (“molecular mimicry”).

3. The third hypothesis suggests that viral infections incurred early in life (“predisposing virus”) might persist in the tissue of interest, and subsequent re-infection with a related virus (“precipitating virus”) that shares antigenic epitopes leads to an immune response against the infected islet cells. This last mechanism, also known as “viral déj vu,” might explain the latency between infections and the onset of diabetes

What is the fundamental immune abnormality in type 1 diabetes?

Failure of self-tolerance in T-cells.

Where does the initial activation of autoreactive T cell occur in DM1?

2. Lipoatrophic diabetes is hyperglycemia accompanied by loss of adipose tissue in the subcutaneous fat. This rare group of genetic disorders has in common insulin resistance, diabetes, hypertriglyceridemia, acanthosis nigricans, and abnormal fat deposition in the liver (hepatic steatosis). Dominant-negative mutations in the DNA-binding domain of PPARG are found in a subset of patients, which interfere with the function of wild-type PPARγ in the nucleus, leading to severe insulin resistance.

What is the key mediator in the pathogenesis of the long-term complications of diabetes?

Persistent hyperglycemia

What are the mediators of the effect of persistent hyperglycemia on tissues?

Formation of Advanced Glycation End Products

Activation of Protein Kinase C.

Intracellular Hyperglycemia and Disturbances in Polyol Pathways.

What is AGE?

Nonenzymatic reactions between intracellular glucose-derived dicarbonyl precursors (glyoxal, methylglyoxal, and 3deoxyglucosone) with the amino groups of both intracellular and extracellular proteins

4)AGE-modified matrix components also trap nonglycated plasma or interstitial proteins. In large vessels, trapping of LDL, for example, retards its efflux from the vessel wall and enhances the deposition of cholesterol in the intima, thus accelerating atherogenesis

5)In capillaries, including those of renal glomeruli, plasma proteins such as albumin bind to the glycated basement membrane, accounting in part for the basement membrane thickening that is characteristic of diabetic microangiopathy.

What are the major complications of DM mediated by AGE?

Macrovascular, Nephropathy

How is PKC activated in diabetes?

Intracellular hyperglycemia stimulates the de novo synthesis of DAG from glycolytic intermediates, and hence causes activation of PKC.

5) Production of pro-inflammatory cytokines by the vascular endothelium

PKC inhibitors might be beneficial in which diabetic complications?

Ruboxistaurin have yielded promising results in diabetic retinopathy and nephropathy

What is the major underlying cause of diabetic neuropathy?

Persistent hyperglycemia

How can disturbances in polyol pathway impair tissue function in DM?

In some tissues that do not require insulin for glucose transport (e.g., nerves, lenses, kidneys, blood vessels), persistent hyperglycemia in the extracellular milieu leads to an increase in intracellular glucose. This excess glucose is metabolized by the enzyme aldose reductase to sorbitol, a polyol, and eventually to fructose, in a reaction that uses NADPH as a cofactor. Progressive depletion of intracellular NADPH by aldol reductase compromises GSH regeneration, increasing cellular susceptibility to oxidative stress.

What are the major changes in pancreas of patients with DM1?

Reduction in the number and size of islets

Leukocytic infiltrates in the islets (insulitis) are principally composed of T lymphocytes. The distribution of insulitis may be strikingly uneven. Eosinophilic infiltrates in diabetic infants who fail to survive the immediate postnatal period.

What are the major changes in the pancreas of patients with DM2?

Subtle reduction in islet cell mass, demonstrated only by special morphometric studies.

Amyloid deposition within islets in type 2 diabetes begins in and around capillaries and between cells. fibrosis may also be observed. Similar lesions may be found in elderly nondiabetics, apparently as part of normal aging.

What is the major changes in the pancreas of nondiabetic newborns of diabetic mothers?

An increase in the number and size of islets

What is the hallmark of diabetic macrovascular disease?

accelerated atherosclerosis

What is the mcc of death in diabetes?

MI

What are the major consequences of macrovascular complications in DM?

MI

CVA

PAD

Hyaline arteriolosclerosis

What is the effect of DM on basement membranes?

One of the most consistent morphologic features of diabetes is diffuse thickening of basement membranes. The thickening is most evident in the capillaries of the skin, skeletal muscle, retina, renal glomeruli, and renal medulla.

However, it may also be seen in such nonvascular structures as renal tubules, the Bowman capsule, peripheral nerves, and placenta.

Despite the increase in the thickness of basement membranes,diabetic capillaries are more leaky than normal to plasma proteins.

What are the characteristic of deposits of Diffuse Mesangial Sclerosis in diabetes?

It is PAS+

What are the histological features of Nodular Glomerulosclerosis?

Ovoid or spherical, often laminated, nodules of matrix situated in the periphery of the glomerulus.

The nodules are PAS-positive.

They lie within the mesangial core of the glomerular lobules

The nodules often show features of mesangiolysis with fraying of the mesangial/capillary lumen interface, disruption of sites at which the capillaries are anchored into the mesangial stalks, and resultant capillary microaneurysm

Even uninvolved lobules and glomeruli show striking diffuse mesangial sclerosis.

As the disease advances, the individual nodules enlarge and may eventually compress and engulf capillaries, obliterating the glomerular tuft.